[unreadable] [unreadable] The primary goal of this project is to understand the transcriptional regulation of Notch-responsive genes. The Notch pathway is critical for determining cell types in developing animals. Alterations of genes in the Notch pathway lead to a number of human diseases including tumor production, CADASIL, Allagilles syndrome, and Alzheimer's Disease. By understanding the molecular mechanisms regulating the genes targeted by Notch it will be possible to clearly determine the mechanisms in diseases caused by mutations in Notch pathway members and to develop cures or treatments for these diseases. The genetic model system, Drosophila melanogaster, will be used in this study. The proposed experiments will identify previously undiscovered regulatory sequences upstream of two of the downstream targets of Notch, Enhancer of split (E(spl)) mgamma and mbeta. Deletion analysis and reporter gene constructs will be used to uncover these regulatory sequences. Transcription factors that interact with these regulatory regions will be identified using a Yeast One-hybrid screen and an Enhancer P-element screen. Finally, identified regulatory transcription factors will be characterized to determine where and when they are expressed during development and how they interact with other transcription factors to regulate E(spl) mgamma and mbetab expression. These basic studies on the regulation of the E(spl) genes will advance the understanding of downstream targets of the disease-related Notch signaling pathway and of the basic mechanisms of combinatorial transcriptional regulation, which is central to the well being of all living organisms. [unreadable] [unreadable] [unreadable]